Abstract
BackgroundEndometriosis, characterized by the presence of functional endometrial tissues outside the uterus, is one of the most common gynecological disorders. Endometrial mesenchymal stem cells (MSCs) are crucial for the occurrence and development of endometriosis. Ectopic endometrial MSCs exist in the peritoneal cavity. Thus, the bioactive factors in endometriotic peritoneal fluid may regulate the biological behaviors of endometrial MSCs.MethodsIn this study, after assessing the concentration of Activin A in peritoneal fluid using ELISA, we isolated and cultured endometrial MSCs and investigated whether Activin A stimulated endometrial MSCs to differentiate into myofibroblasts and clarified the underlying mechanisms by quantitative real-time PCR, Western blot analysis, immunofluorescent staining, RNA interference and Chromatin immunoprecipitation. We also employed the inhibitors of Activin A to explore the possibility of suppressing the development of fibrosis in endometriosis using primary endometrial MSCs cultures and a mouse model of endometriosis.ResultsHere, we revealed that Activin A significantly elevated in endometriotic peritoneal fluid and activin receptor-like kinase (ALK4), the specific receptor for Activin A, obviously enhanced in ectopic endometrial MSCs compared with eutopic endometrial MSCs from women with or without endometriosis. Next, we found that Activin A drived myofibroblast differentiation of endometrial MSCs, with extremely enhanced expression of connective tissue growth factor (CTGF). CTGF was shown to be required for Activin A-induced expression of ACTA2, COL1A1 and FN1 in endometrial MSCs. CTGF induction by Activin A in endometrial MSCs involved the activation of Smad2/3, as evidenced by the phosphorylation and nuclear translocation of Smad2/3 as well as the binding of Smad2/3 to CTGF promoter. Furthermore, Smad/CTGF pathway in endometrial MSCs required activation of STAT3 while independent of PI3K, JNK and p-38 pathways. In addition, we also demonstrated that inhibition of Activin A pathway impeded myofibroblast differentiation of endometrial MSCs and ameliorated fibrosis in endometriosis mice.ConclusionsActivin A promotes myofibroblast differentiation of endometrial mesenchymal stem cells via STAT3-dependent Smad/CTGF pathway. The results provided the first evidence that STAT3 acted as a crucial Activin A downstream mediator to regulate CTGF production. Our data may supplement the stem cell theory of endometriosis and provide the experimental basis to treat endometriosis-associated fibrosis by manipulating Activin A signaling.
Highlights
Endometriosis, characterized by the presence of functional endometrial tissues outside the uterus, is one of the most common gynecological disorders
Activin a elevated in endometriotic peritoneal fluid and ectopic endometrial mesenchymal stem cells (MSCs) expressed elevated level of activin receptor-like kinase (ALK4) Hou et al reported that Activin A increased to 88.74 times in peritoneal fluid of women with endometriosis when compared to women without based on a cytokine array analysis [12]
We compared the expression of ALK4, the specific receptor for Activin A, in cultured paired eutopic and ectopic endometrial MSCs derived from patients with endometriosis as well as eutopic endometrial MSCs derived from patients without endometriosis
Summary
Endometriosis, characterized by the presence of functional endometrial tissues outside the uterus, is one of the most common gynecological disorders. Endometrial mesenchymal stem cells (MSCs) are crucial for the occurrence and development of endometriosis. The bioactive factors in endometriotic peritoneal fluid may regulate the biological behaviors of endometrial MSCs. Endometriosis, histologically characterized by dense fibrosis in and surrounding the endometriotic lesions, is one of the most common gynecological disorders affecting 10–15% of all women of reproductive age [1]. Endometrial MSCs derived from endometriosis patients express increased extracellular matrix proteolysis genes in comparation with normal women [3]. We recently found that ectopic endometrial MSCs expressed elevated fibrotic proteins, including collagen I, α-smooth muscle actin (α-SMA), fibronectin, and connective tissue growth factor (CTGF), compared with eutopic endometrial MSCs from women with or without endometriosis and that endometriotic peritoneal fluid promotes myofibroblast differentiation of endometrial MSCs (In Press). Studies aimed at clarifying the underlying mechanisms of myofibroblast differentiation of endometrial MSCs are expected to provide a novel strategy for treatment of endometriosis
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